Process Wednesday: large-scale fluorination

Hot off the Organic Process Research and Development presses is an interesting fluorocyclobutane molecule from a group at Pfizer. [1] It's synthesized from the reaction of a magnesium ate complex with a cyclobutanone in a flow reactor (which is all interesting in its own right.) But I wanted to note the screening of fluorination reagents, especially since it doesn't seem like there are a lot of examples of large-scale fluorination in OPRD. Fluorination is interesting to me, because it seems like your choices are 1) to work with hazardous reagents like HF or DAST or 2) to use fluorinating reagents like Deoxo-Fluor, for which you will pay a premium.

From the text:

The original scale-up conditions for the fluorination reaction involved treatment of 5 with 1.5−1.8 equiv of Deoxo-Fluor (27) at −78 °C in methylene chloride or THF to furnish 2. While the ratio of diastereomers (2:3) was ∼8:1, the need to use, and subsequently quench, an excess of Deoxo-Fluor, coupled with the need for cryogenic equipment prompted us to explore alternative conditions. Several deoxofluorination conditions were evaluated for the conversion of tertiary alcohol 5 to the free-base form of API, 2. These included not only other fluorinating reagents but also involved attempts to render the Deoxo-Fluor amenable to scale-up in noncryogenic vessels.

The authors explore their results, which I've partially summarized with the altered graphic below. (I've not used any of the other reagents other than Deoxo-Fluor, so I don't have experience with them.) It's interesting that both DFI and TFFH suffer from an inability to purge the urea byproduct, even after aqueous wash and isolation of product.

Credit: Hawkins et al., Org. Process Res. Dev.

The authors were ultimately able to find that only 1.1 equivalents of Deoxo-Fluor at 0°C were required to give adequate yields of product. They added the reaction mixture into their aqueous potassium carbonate/MeTHF (how's that for specific!?!) quench solution at -10°C to 0°C. "Adequate mixing during the quench was important to prevent localized accumulation of hydrofluoric acid, which could degrade the product. Experimental evidence suggested that a final aqueous pH 10−11 was ideal to ensure that all of the hydrofluoric acid had been quenched and converted to potassium fluoride and to ensure that the desired product resided in the organic layer."

A pretty cool paper, I think.

[1] Hawkins, J.M.; Dubé, P.; Maloney, M.T.;Wei, L.; Ewing, M.; Chesnut, S.M.; Denette, J.R.; Lillie, B.M.; Vaidyanathan, R. "Synthesis of an H3 Antagonist via Sequential One-Pot Additions of a Magnesium Ate Complex and an Amine to a 1,4-Ketoester followed by Carbonyl-Directed Fluoride Addition." Org. Process Res. Dev., Article ASAP DOI: 10.1021/op300093j